How to Assess Fibrinogen Levels and Fibrin Clot Properties in Clinical Practice?

 

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Abstract

Fibrin formed from fibrinogen is the main component of thrombi. Clot structure is characterized by fiber thickness and pore size, which differs within a given clot and between individuals. Plasma clot architecture is largely determined by the quantity and quality of fibrinogen. Plasma fibrinogen concentrations are most commonly measured in citrated plasma using the Clauss method. However, several factors, including instrument type and reagent, may affect results. Other approaches to express the ability of fibrinogen to clot involve prothrombin time–derived or clottable protein assays, while fibrinogen antigen levels in clinical settings are measured using immunological or precipitation assays. Fibrin clot permeability (reflected by the Darcy constant, K _s) being proportional to a buffer volume percolating through a clot under a given hydrostatic pressure is now the most commonly used measure of clot structure. Low K _s values indicating tightly packed fibrin structure have been shown to be associated with venous and arterial thrombotic complications, while high K _s might contribute to bleeding disorders. The measurement of K _s, however, is not standardized and validated. This review summarizes the current knowledge on practical aspects of the measurement of fibrinogen levels and K _s in patients.

• References

• 1 Weisel JW, Litvinov RI. Mechanisms of fibrin polymerization and clinical implications. Blood 2013; 121 (10) 1712-1719
  CrossrefPubMedGoogle Scholar
• 2 Komáromi I, Bagoly Z, Muszbek L. Factor XIII: novel structural and functional aspects. J Thromb Haemost 2011; 9 (1) 9-20
  CrossrefPubMedGoogle Scholar
• 3 Lord ST. Fibrinogen and fibrin: scaffold proteins in hemostasis. Curr Opin Hematol 2007; 14 (3) 236-241
  CrossrefPubMedGoogle Scholar
• 4 Mackie IJ, Kitchen S, Machin SJ, Lowe GD ; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on fibrinogen assays. Br J Haematol 2003; 121 (3) 396-404
  CrossrefPubMedGoogle Scholar
• 5 Whitton CM, Sands D, Hubbard AR, Gaffney PJ. A collaborative study to establish the 2nd International Standard for Fibrinogen, Plasma. Thromb Haemost 2000; 84 (2) 258-262
  PubMedGoogle Scholar
• 6 Chandler WL. Initial evaluation of hemostasis: reagent and method selection. In: Kitchen S, Olson JD, Preston FE, eds. Quality in Laboratory Hemostasis and Thrombosis. Oxford: Wiley-Blackwell; 2009: 63-71
  CrossrefGoogle Scholar
• 7 Miesbach W, Schenk J, Alesci S, Lindhoff-Last E. Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia. Thromb Res 2010; 126 (6) e428-e433
  CrossrefPubMedGoogle Scholar
• 8 Oosting JD, Hoffmann JJ. Evaluation of an automated photometric fibrinogen assay. Blood Coagul Fibrinolysis 1997; 8 (6) 321-326
  CrossrefPubMedGoogle Scholar
• 9 Lawrie AS, McDonald SJ, Purdy G, Mackie IJ, Machin SJ. Prothrombin time derived fibrinogen determination on Sysmex CA-6000. J Clin Pathol 1998; 51 (6) 462-466
  CrossrefPubMedGoogle Scholar
• 10 De Cristofaro R, Landolfi R. Measurement of plasma fibrinogen concentration by the prothrombin-time-derived method: applicability and limitations. Blood Coagul Fibrinolysis 1998; 9 (3) 251-259
  CrossrefPubMedGoogle Scholar
• 11 Llamas P, Santos AB, Outeiriño J, Soto C, Tomás JF. Diagnostic utility of comparing fibrinogen Clauss and prothrombin time derived method. Thromb Res 2004; 114 (1) 73-74
  CrossrefPubMedGoogle Scholar
• 12 Sobas F, Hanss M, Ffrench P, Trzeciak MC, Dechavanne M, Négrier C. Human plasma fibrinogen measurement derived from activated partial thromboplastin time clot formation. Blood Coagul Fibrinolysis 2002; 13 (1) 61-68
  CrossrefPubMedGoogle Scholar
• 13 Jensen T, Halvorsen S, Godal HC, Sandset PM, Skjøonsberg OH. Discrepancy between fibrinogen concentrations determined by clotting rate and clottability assays during the acute-phase reaction. Thromb Res 2000; 100 (5) 397-403
  CrossrefPubMedGoogle Scholar
• 14 Cunningham MT, Brandt JT, Laposata M, Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med 2002; 126 (4) 499-505
  PubMedGoogle Scholar
• 15 Peters SA, Woodward M, Rumley A, Koenig W, Tunstall-Pedoe H, Lowe GD. Direct comparisons of three alternative plasma fibrinogen assays with the von Clauss assay in prediction of cardiovascular disease and all-causes mortality: the Scottish Heart Health Extended Cohort. Br J Haematol 2013; 162 (3) 392-399
  CrossrefPubMedGoogle Scholar
• 16 Farrell DH. γ' Fibrinogen as a novel marker of thrombotic disease. Clin Chem Lab Med 2012; 50 (11) 1903-1909
  PubMedGoogle Scholar
• 17 Harr JN, Moore EE, Ghasabyan A , et al. Functional fibrinogen assay indicates that fibrinogen is critical in correcting abnormal clot strength following trauma. Shock 2013; 39 (1) 45-49
  PubMedGoogle Scholar
• 18 Carroll RC, Craft RM, Chavez JJ, Snider CC, Kirby RK, Cohen E. Measurement of functional fibrinogen levels using the Thrombelastograph. J Clin Anesth 2008; 20 (3) 186-190
  CrossrefPubMedGoogle Scholar
• 19 Weisel JW. Structure of fibrin: impact on clot stability. J Thromb Haemost 2007; 5 (Suppl. 01) 116-124
  CrossrefPubMedGoogle Scholar
• 20 Blombäck B, Carlsson K, Fatah K, Hessel B, Procyk R. Fibrin in human plasma: gel architectures governed by rate and nature of fibrinogen activation. Thromb Res 1994; 75 (5) 521-538
  CrossrefPubMedGoogle Scholar
• 21 Carr ME. Fibrin formed in plasma is composed of fibers more massive than those formed from purified fibrinogen. Thromb Haemost 1988; 59 (3) 535-539
  PubMedGoogle Scholar
• 22 Dunn EJ, Ariëns RA, de Lange M , et al. Genetics of fibrin clot structure: a twin study. Blood 2004; 103 (5) 1735-1740
  CrossrefPubMedGoogle Scholar
• 23 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21 (3) 131-142
  CrossrefPubMedGoogle Scholar
• 24 Hethershaw EL, Cilia La Corte AL, Duval C , et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost 2014; 12 (2) 197-205
  CrossrefPubMedGoogle Scholar
• 25 Carr Jr ME, Shen LL, Hermans J. Mass-length ratio of fibrin fibers from gel permeation and light scattering. Biopolymers 1977; 16 (1) 1-15
  CrossrefPubMedGoogle Scholar
• 26 Blombäck B, Okada M. Fibrin gel structure and clotting time. Thromb Res 1982; 25 (1–2) 51-70
  CrossrefPubMedGoogle Scholar
• 27 Mills JD, Ariëns RA, Mansfield MW, Grant PJ. Altered fibrin clot structure in the healthy relatives of patients with premature coronary artery disease. Circulation 2002; 106 (15) 1938-1942
  CrossrefPubMedGoogle Scholar
• 28 Undas A, Szułdrzynski K, Stepien E , et al. Reduced clot permeability and susceptibility to lysis in patients with acute coronary syndrome: effects of inflammation and oxidative stress. Atherosclerosis 2008; 196 (2) 551-557
  CrossrefPubMedGoogle Scholar
• 29 Undas A, Podolec P, Zawilska K , et al. Altered fibrin clot structure/function in patients with cryptogenic ischemic stroke. Stroke 2009; 40 (4) 1499-1501
  CrossrefPubMedGoogle Scholar
• 30 Okada M, Blombäck B. Factors influencing fibrin gel structure studied by flow measurement. Ann N Y Acad Sci 1983; 408: 233-253
  CrossrefPubMedGoogle Scholar
• 31 Sjøland JA. A new optimized method for the determination of fibrin clot permeability. Blood Coagul Fibrinolysis 2005; 16 (8) 579-583
  CrossrefPubMedGoogle Scholar
• 32 Pieters M, Undas A, Marchi R, De Maat MP, Weisel J, Ariëns RA ; Factor XIII And Fibrinogen Subcommittee Of The Scientific Standardisation Committee Of The International Society For Thrombosis And Haemostasis. An international study on the standardization of fibrin clot permeability measurement: methodological considerations and implications for healthy control values. J Thromb Haemost 2012; 10 (10) 2179-2181
  CrossrefPubMedGoogle Scholar
• 33 Ząbczyk M, Piłat A, Awsiuk M, Undas A. An automated method for fibrin clot permeability assessment. Blood Coagul Fibrinolysis 2015; 26 (1) 104-109
  CrossrefPubMedGoogle Scholar
• 34 Collet JP, Montalescot G, Lesty C , et al. Disaggregation of in vitro preformed platelet-rich clots by abciximab increases fibrin exposure and promotes fibrinolysis. Arterioscler Thromb Vasc Biol 2001; 21 (1) 142-148
  CrossrefPubMedGoogle Scholar
• 35 Blombäck M, He S, Bark N, Wallen HN, Elg M. Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. Br J Haematol 2011; 152 (6) 758-765
  CrossrefPubMedGoogle Scholar
• 36 He S, Blombäck M, Bark N, Johnsson H, Wallén NH. The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis. Thromb Haemost 2010; 103 (5) 1076-1084
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Ząbczyk M, Blombäck M, Majewski J , et al. Assays of fibrin network properties altered by VKAs in atrial fibrillation - importance of using an appropriate coagulation trigger. Thromb Haemost 2015; 113 (4) 851-861
  PubMedGoogle Scholar
• 38 Sadowski M, Ząbczyk M, Undas A. Coronary thrombus composition: links with inflammation, platelet and endothelial markers. Atherosclerosis 2014; 237 (2) 555-561
  CrossrefPubMedGoogle Scholar
• 39 Undas A, Ariëns RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31 (12) e88-e99
  CrossrefPubMedGoogle Scholar
• 40 Zalewski J, Bogaert J, Sadowski M , et al. Plasma fibrin clot phenotype independently affects intracoronary thrombus ultrastructure in patients with acute myocardial infarction. Thromb Haemost 2015; 113 (6) 1258-1269
  Article in Thieme ConnectPubMedGoogle Scholar
• 41 Undas A. Fibrin clot properties and their modulation in thrombotic disorders. Thromb Haemost 2014; 112 (1) 32-42
  Article in Thieme ConnectPubMedGoogle Scholar
• 42 Collet JP, Soria J, Mirshahi M , et al. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure. Blood 1993; 82 (8) 2462-2469
  PubMedGoogle Scholar
• 43 Hessel B, Silveira AM, Carlsson K , et al. Fibrinogenemia Tampere—a dysfibrinogenemia with defective gelation and thromboembolic disease. Thromb Res 1995; 78 (4) 323-339
  CrossrefPubMedGoogle Scholar
• 44 Jörneskog G, Egberg N, Fagrell B , et al. Altered properties of the fibrin gel structure in patients with IDDM. Diabetologia 1996; 39 (12) 1519-1523
  CrossrefPubMedGoogle Scholar
• 45 Dunn EJ, Ariëns RA, Grant PJ. The influence of type 2 diabetes on fibrin structure and function. Diabetologia 2005; 48 (6) 1198-1206
  CrossrefPubMedGoogle Scholar
• 46 Undas A, Brozek J, Jankowski M, Siudak Z, Szczeklik A, Jakubowski H. Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol 2006; 26 (6) 1397-1404
  CrossrefPubMedGoogle Scholar
• 47 Mazur P, Sokołowski G, Hubalewska-Dydejczyk A, Płaczkiewicz-Jankowska E, Undas A. Prothrombotic alterations in plasma fibrin clot properties in thyroid disorders and their post-treatment modifications. Thromb Res 2014; 134 (2) 510-517
  CrossrefPubMedGoogle Scholar
• 48 He S, Cao H, Antovic A, Blombäck M. Modifications of flow measurement to determine fibrin gel permeability and the preliminary use in research and clinical materials. Blood Coagul Fibrinolysis 2005; 16 (1) 61-67
  CrossrefPubMedGoogle Scholar
• 49 Undas A, Nowakowski T, Cieśla-Dul M, Sadowski J. Abnormal plasma fibrin clot characteristics are associated with worse clinical outcome in patients with peripheral arterial disease and thromboangiitis obliterans. Atherosclerosis 2011; 215 (2) 481-486
  CrossrefPubMedGoogle Scholar
• 50 Zalewski J, Undas A, Godlewski J, Stepien E, Zmudka K. No-reflow phenomenon after acute myocardial infarction is associated with reduced clot permeability and susceptibility to lysis. Arterioscler Thromb Vasc Biol 2007; 27 (10) 2258-2265
  CrossrefPubMedGoogle Scholar
• 51 Undas A, Zalewski J, Krochin M , et al. Altered plasma fibrin clot properties are associated with in-stent thrombosis. Arterioscler Thromb Vasc Biol 2010; 30 (2) 276-282
  CrossrefPubMedGoogle Scholar
• 52 Undas A, Slowik A, Wolkow P, Szczudlik A, Tracz W. Fibrin clot properties in acute ischemic stroke: relation to neurological deficit. Thromb Res 2010; 125 (4) 357-361
  CrossrefPubMedGoogle Scholar
• 53 Palka I, Nessler J, Nessler B, Piwowarska W, Tracz W, Undas A. Altered fibrin clot properties in patients with chronic heart failure and sinus rhythm: a novel prothrombotic mechanism. Heart 2010; 96 (14) 1114-1118
  CrossrefPubMedGoogle Scholar
• 54 Drabik L, Wołkow P, Undas A. Denser plasma clot formation and impaired fibrinolysis in paroxysmal and persistent atrial fibrillation while on sinus rhythm: association with thrombin generation, endothelial injury and platelet activation. Thromb Res 2015; 136 (2) 408-414
  CrossrefPubMedGoogle Scholar
• 55 Rajzer M, Wojciechowska W, Kawecka-Jaszcz K, Undas A. Plasma fibrin clot properties in arterial hypertension and their modification by antihypertensive medication. Thromb Res 2012; 130 (1) 99-103
  CrossrefPubMedGoogle Scholar
• 56 Undas A, Zawilska K, Ciesla-Dul M , et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114 (19) 4272-4278
  CrossrefPubMedGoogle Scholar
• 57 Siudut J, Świat M, Undas A. Altered fibrin clot properties in patients with cerebral venous sinus thrombosis: association with the risk of recurrence. Stroke 2015; 46 (9) 2665-2668
  CrossrefPubMedGoogle Scholar
• 58 Sjøland JA, Sidelmann JJ, Brabrand M , et al. Fibrin clot structure in patients with end-stage renal disease. Thromb Haemost 2007; 98 (2) 339-345
  PubMedGoogle Scholar
• 59 Undas A, Kolarz M, Kopeć G, Tracz W. Altered fibrin clot properties in patients on long-term haemodialysis: relation to cardiovascular mortality. Nephrol Dial Transplant 2008; 23 (6) 2010-2015
  CrossrefPubMedGoogle Scholar
• 60 Gronostaj K, Richter P, Nowak W, Undas A. Altered plasma fibrin clot properties in patients with digestive tract cancers: links with the increased thrombin generation. Thromb Res 2013; 131 (3) 262-267
  CrossrefPubMedGoogle Scholar
• 61 Undas A, Zubkiewicz-Usnarska L, Helbig G , et al. Altered plasma fibrin clot properties and fibrinolysis in patients with multiple myeloma. Eur J Clin Invest 2014; 44 (6) 557-566
  CrossrefPubMedGoogle Scholar
• 62 Małecki R, Gacka M, Kuliszkiewicz-Janus M , et al. Altered plasma fibrin clot properties in essential thrombocythemia. Platelets 2015; ; In press
  PubMedGoogle Scholar
• 63 Owczarek D, Cibor D, Sałapa K, Głowacki MK, Mach T, Undas A. Reduced plasma fibrin clot permeability and susceptibility to lysis in patients with inflammatory bowel disease: a novel prothrombotic mechanism. Inflamm Bowel Dis 2013; 19 (12) 2616-2624
  CrossrefPubMedGoogle Scholar
• 64 Vikerfors A, Svenungsson E, Ågren A , et al. Studies of fibrin formation and fibrinolytic function in patients with the antiphospholipid syndrome. Thromb Res 2014; 133 (5) 936-944
  CrossrefPubMedGoogle Scholar
• 65 Celińska-Lowenhoff M, Iwaniec T, Padjas A, Musiał J, Undas A. Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation. Thromb Haemost 2014; 112 (2) 287-296
  Article in Thieme ConnectPubMedGoogle Scholar
• 66 Kwasny-Krochin B, Gluszko P, Undas A. Unfavorably altered fibrin clot properties in patients with active rheumatoid arthritis. Thromb Res 2010; 126 (1) e11-e16
  CrossrefPubMedGoogle Scholar
• 67 Ariëns RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, Grant PJ. The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 2000; 96 (3) 988-995
  CrossrefPubMedGoogle Scholar
• 68 Undas A, Stepien E, Tracz W, Szczeklik A. Lipoprotein(a) as a modifier of fibrin clot permeability and susceptibility to lysis. J Thromb Haemost 2006; 4 (5) 973-975
  CrossrefPubMedGoogle Scholar
• 69 Williams S, Fatah K, Hjemdahl P, Blombäck M. Better increase in fibrin gel porosity by low dose than intermediate dose acetylsalicylic acid. Eur Heart J 1998; 19 (11) 1666-1672
  CrossrefPubMedGoogle Scholar
• 70 Woodhead JL, Nagaswami C, Matsuda M, Arocha-Piñango CL, Weisel JW. The ultrastructure of fibrinogen Caracas II molecules, fibers, and clots. J Biol Chem 1996; 271 (9) 4946-4953
  CrossrefPubMedGoogle Scholar
• 71 Undas A, Celinska-Löwenhoff M, Löwenhoff T, Szczeklik A. Statins, fenofibrate, and quinapril increase clot permeability and enhance fibrinolysis in patients with coronary artery disease. J Thromb Haemost 2006; 4 (5) 1029-1036
  CrossrefPubMedGoogle Scholar
• 72 Gajos G, Zalewski J, Rostoff P, Nessler J, Piwowarska W, Undas A. Reduced thrombin formation and altered fibrin clot properties induced by polyunsaturated omega-3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (OMEGA-PCI clot). Arterioscler Thromb Vasc Biol 2011; 31 (7) 1696-1702
  CrossrefPubMedGoogle Scholar
• 73 Szczepaniak P, Zabczyk M, Undas A. Increased plasma clot permeability and susceptibility to lysis are associated with heavy menstrual bleeding of unknown cause: a case-control study. PLoS ONE 2015; 10 (4) e0125069
  CrossrefPubMedGoogle Scholar
• 74 Ząbczyk M, Hońdo Ł, Krzek M, Undas A. High-density cholesterol and apolipoprotein AI as modifiers of plasma fibrin clot properties in apparently healthy individuals. Blood Coagul Fibrinolysis 2013; 24 (1) 50-54
  CrossrefPubMedGoogle Scholar